1. Field of the Invention
This invention relates to instruments that require calibration to make measurements on animal tissues or other materials, and in particular, to measurement instruments that utilize a removable calibration device that ensures proper calibration of the measurement instrument. The invention also relates to apparatus and methods of determining a bilirubin concentration in a human's blood.
2. Background of the Related Art
Spectroscopy is currently used for a wide variety of purposes including evaluation of in-vivo or in-vitro tissue samples. One type of spectroscopy, reflectance spectroscopy, involves diffusely reflecting light from tissue, non-invasively, and analyzing the reflected light. Such spectroscopic devices must be calibrated prior to use, especially when made for medical or other critical applications. Instrument calibration can be affected by variations in light source intensity, spectral characteristics, lens-aging, lens cleanliness, temperature, detector sensitivity changes, and electronic drifting.
More generally, there has been an increase in the use of light as a diagnostic tool in many areas of medicine. This development has become more pervasive with the development of appropriate and inexpensive light sources, detection devices and optical fibers that allow for minimal invasiveness.
Typically, spectral transmittance, fluorescence (normal and time resolved) and Raman spectroscopy are used to evaluate biological tissues and other materials in order to determine the materials present and to measure their concentrations. These methods are affected by the scattering, reflecting, absorbing and transmitting properties of the instrument optics, detectors, sources and the media under examination. This is due to the fact that the amount of light reaching the tissue to be measured is a function of those parameters, and in the case of fluorescence and Raman emissions, re-absorption of emission spectra.
Acoustic type measuring systems are also used for a wide variety of purposes including to evaluate tissue or materials. Acoustic measurement systems also experience variations in the output energy of the acoustic wave source, changes in spectral characteristics of the tissue or material due to changes in temperature, detector sensitivity changes, and electronic drifting.
Many of the above-described types of measurement systems require calibrations to be performed on a routine basis in order to compensate for changes in instrument performance and response. This is true for both radiation based measurement systems, i.e., systems that reflect electromagnetic radiation from the tissue or material to be measured and then analyze the return radiation, and acoustic based measurement systems, i.e., systems that reflect acoustic waves or energy from the tissue or material to be measured and then analyze the return acoustic signal.
Calibration techniques typically involve measuring the response of a test target with characteristics that remain stable over time and over a range of temperatures. Those calibration techniques can also be used to compensate for instrument to instrument variations, and for any changes that an individual instrument may experience over its working lifetime.
Although others have proposed calibration fixtures that compensate for these variations in instrument performance, none have provided a simultaneous solution to both the calibration issue and the problems associated with the spread of infection in a medical setting. Furthermore, calibration devices that are designed to be reused can become damaged by sunlight, temperature, humidity and other effects, which could lead to errors in calibration.
Various types of calibration techniques and devices have been attempted. For example, U.S. Pat. No. 5,365,925 describes a calibration boot which includes a plurality of materials, which is placed over an optical catheter for the purpose of making a multi-point calibration of reflected or backscattered light. U.S. Pat. No. 5,311,273 describes a method of using four black body radiators to provide calibration of an infrared spectrometer. However, neither of these approaches involves an inexpensive calibration target that can be easily discarded after each use. In addition, neither of these systems prevent a user from taking a measurement without going through a calibration step.
U.S. Pat. No. 4,981,355 describes a calibration device for the in vitro calibration of a light guide, whereby a polyethylene material has a plurality of light scattering particles and a plurality of light absorbing particles which yields a neutral density filtering type of effect, uniformly distributing light in the plastic parts of the calibrator. The calibrator can be positioned into a sterile tray which is protected by a tear off plastic. Once the calibration is complete, the surgeon removes the catheter from the calibrator and the tray in which it is held and then presumably disposes of the calibration device and its tray. This approach, however, is neither simple nor inexpensive.
U.S. Pat. No. 4,796,633 describes a calibration reference apparatus that fits over a light guide. A stop limits the extent to which the light guide can be advanced into the cavity, whereby an endface of the light guide is spaced from a region of the surface to define a gap. The end wall and the gap are adapted to return a known ratio of the light directed into the gap from the end face of the light guide. Again, however, this approach does not involve an inexpensive, disposable calibration device.
U.S. Pat. No. 4,744,656 discloses a calibration boot that snaps into place over an optical catheter allowing calibration of the catheter before use. Once the calibration is complete, the boot is removed and the optical catheter is ready for use. Each new catheter comes with a new boot. However, the boot is not present during the measurement and there is no provision to prevent reuse of the boot.
One application of spectroscopic systems involves detection of a bilirubin concentration in a human. Bilirubin is produced from the breakdown of hemoglobin in red blood cells. Under normal conditions, the bilirubin is conjugated by glucoronyl transferase, an enzyme present in the liver, and is then excreted through the biliary system.
Newborn infants and prematurely born infants are particularly susceptible to hyperbilirubinemia. Hyperbilirubinemia describes the state where there is excessive bilirubin in the body. Often this is due to the lack of functioning glucoronyl transferase enzyme in their liver, or excessive red blood cell breakdown associated with erythroblastosis fetalis.
One method for bilirubin testing includes blood based lab assay testing. The “heel stick” blood lab assay is currently the only accepted methodology for quantitative bilirubin testing results in the United States. Of course, this invasive approach requires that blood be drawn to perform the test.
Non-invasive measurements of the bilirubin concentration would eliminate the need to draw blood samples from patients for bilirubin analysis. It would also provide easy patient interface. It is known that bilirubin can be measured non-invasively by taking reflectance measurements from a patient's skin, from the aqueous of the eye, or from the sclera (white) of the eye, based on the fluorescent signature. Reflectance measurements can also be made on the tympanic membrane of the ear. This is possible because bilirubin from the blood stains the skin as well as other tissues of the body. Jaundice refers to the condition when the bilirubin is visible in the skin and sclera.
Many attempts have been made to measure cutaneous bilirubin non-invasively. These attempts include the development of visual reference standards, and transcutaneous reflectance spectroscopy to measure the absorption spectra of bilirubin, oxidized blood, and melanin, the dominant absorbers in the skin. The concentration of these pigments have distinct absorption spectra.
Reflectance bilirubinometers have obtained reasonable correlations between bilirubin levels determined transcutaneously and serum bilirubin concentrations in homogeneous patient populations. Unfortunately, these devices have failed to give satisfactory correlations when used over a heterogeneous population. Since patient populations are rarely homogeneous, transcutaneous bilirubin measuring methods have not been widely accepted clinically.
One known system, which implements a non-invasive cutaneous testing approach for bilirubin and is in wide use in Japan, is the Minolta Jaundice Meter. That approach, however, has not been approved for use in the United States, although it is used for screening purposes in some U.S. institutions. In addition, that approach does not account for variations in skin color and thickness.
Another approach to testing for bilirubin that does not require the drawing of blood is a breath analysis approach introduced by a group from Stanford. This approach does not have a quantitative accuracy required to have a high correlation to serum bilirubin. Hence, it appears to only have potential use as a screening technique.